Pharmaceutical composition containing phenylbutazone derivative



United States Patent ce 3,4911%" Patented Jan. 20, 1970 It has beenfound that it is possible to prepare from 3,491,190 these two compoundsa product which is the result of PHARMACEUTICAL COMPOSITION CONTAININGtheir addition in equimolecular proportion and which oc- PHENYLBUTAZONEDERIVATIVE curs in the crystalline state with water of crystallisation,2 2 35 g af ggt fig k ig fifigf gg gg either at a level of one molwhenit is prepared in aque- Rafiet a of Finis France ous acetone, orimmediately at a rate of two mols, when No Drawing. Original applicationAug. 26, 1966, S r it is prepared, for instance, in dimethyl formamide,the No. 575,248. Divided and this application Mal. 6, 1968, one-molproduct gradually hydratlng, lwlth no change 1n Ser. No. 729,851 meltingpoint, into the dihydrated form which is, ap- Claims priority,application France, Sept. 8, 1965, 10 parently, the stable form.

2 This product has the general Formula III which fol- Int. Cl. A61k27/00; A611 23/00 us. (:1. 424-273 4 Claims lows:

I (-i n-H C4:O

According further to this invention, there is provided a 25 process forthe production of a compound of Formula ABSTRACT OF THE DISCLOSURE IIIwhich comprises reacting clofexamide, in a diluent or 'luents withphenylbutazone. A harmaceutical composition having utility inter aha,mlxture 9 d1 as ail anti-inflammatory agent comprising as the active Thedlluents used m for examp ethyl alcohol increment an effective amount ofa compound having the ethyl acetate, aqueous dioxane, aqueous ethanol,aqueous foimula acetone or aqueous methyl ethyl ketone, or dimethyl i 30= H C [(H5C2)2)CH2CH2NHC OOHrO-Cl], i to 2 H20 11- 9 4 and apharmaceutically acceptable carrier. formamide or methylene chloride. Ina variant of the process clofexamide hydrochloride may be reacted withphenylbutazone in water. The phenylbutazone and clofex- This applicationis a division of my co-pending applicaamide are preferably used insubstantially equimolecular tion, Ser. No. 575,248, filed Aug. 26, 1966.proportions.

This invention relates to therapeutic compositions con- The followingexamples will serve to illustrate the protaining a new derivative ofphenylbutazone. duction of the compounds of the invention:

Phenylbutazone, or 4-n-butyl 3,5-dioxo 1,2-diphenyl pyrazolidine whichhas the Formula I: EXAMPLE 1 (IJGHS 06115 935 g. of phenylbutazone aredissolved, with heating to a lukewarm state, in 2.7 litres of acetonecontaining 20% water, and the mixture is filtered if necessary. 853.5NC6H5 or N CH5 g. of p-chloro phenoxy acetic acid diethylamino ethylmmmamide are dissolved in 300 cc. of acetone containing 20% 1 water, andthe solution is poured into the phenylbutazone H I solution. There isslight heating, and the solution clarifies.

and clofexamide, or p-chloro phenoxy acetic acid B-dieth- The Saltcrystallises p yy g is effected 011 a ylamino ethylamide-which has theFormula Biichner funnel and the mixture is washed in 450 cc. of RC2acetone containing 20% of water. The 1702 g. of product a obtained isrecrystallised in 2450 cc. of acetone contain- N-CHPCHPNHC ing 20% ofwater and, after drying in an oven at 37 C.,

g, 1585 g. (86%) of product are obtained. The product is H in the formof a white crystalline powder having a melting point of from 87 to 89 C.in the Maquenne block.

are known for therapeutic purposes. The product is insoluble in waterand ether and benzene,

853.5 g. of p-chloro phenoxy acetic acid diethylamino ethylamide aredissolved in 1 litre of dimethyl formamide and a solution of 925.5 g. ofphenylbutazone in 1 litre of the same solvent is added, whereafter themixture is diluted with litres of water. The mixture is filtered toisolate the crystallised product which is obtained in this way with a93% yield. After recrystallisation in acetone containing of water, thefinal yield is 79%. The product thus obtained is in its dihydrated form.

EXAMPLE 3 A solution of 284.5 g. of p-chloro phenoxy acetic acidN-diethylamino ethylamide in 1 litre of methylene chloride is mixed witha solution of 308.3 g. of phenylbutazone in 500 cc. of the same solvent.The solvent is distilled and the oily residue taken up by acetone having20% water contents, the product crystallising. The yield is around 85%.

EXAMPLE4 616 g. of phenylbutazone are suspended in 2 litres of aqueousmethyl ethyl ketone. A solution of 568 g. of pchloro phenoxy acetic aciddiethylamino ethylamide in 1 litre of the same solvent is prepared andmixed. The heat evolved in the reaction causes all the phenylbutazone tobe dissolved. The crystallised product is obtained in a 90% yield bycooling. 0

EXAMPLE 5 A suspension of 308.3 g. of phenylbutazone in 1.5 litre of 50%ethyl alcohol has poured into it a lukewarm solution of 284.5 g. ofp-chloro phenoxy acetic acid diethylamine ethylamide in 1 litre of thesame solvent. The crystallised product is isolated from the resultingsolution after cooling, with an 86% yield.

EXAMPLE 6 6.42 g. of p-chloro phenoxy acetic acid diethylaminoethylamide hydrochloride in solution in 35 cc. of water are mixed with6.16 g. of phenylbutazone in solution in 20 cc. of standard caustic sodaand 35 cc. of water. The salt precipitates and gradually crystallises.11.6 of product are obtained. 5

Th novel salt has been tested pharmacologically, with the followingresults.

(l) Toxicological study Toxicological studies were made consecutively inmice and in Wistar stock rats. All the animals were distributed intouniform batches weightwise and sexwise. The water insoluble product wasadministered via the digestive tract in the form of a fine suspension ina dilute solution of Tween 80. The animals were observed for 48 hoursand the lethal dose was calculated by the method of Litchfield andWilcoxon.

(a) Acute toxicity in mice-When administered per os the new salt has aLD of 2000 mg./kg. The slope of the regression line is 5:125 and theconfidence interval for F 005 is between 1754 and 2280 mg./kg. for LDand between 1 and 1.6 for the regression line. By way of comparison, theLD as calculated by the same method was 540 mg./kg. for phenylbutazone.The slope of the regression line is S=1.40. The confidence interval forP=0.05 is between 457 and 657 mg./kg. for LD and between 1.09 and 1.79for the regression line.

(b) Acute toxicity in rats.-The overall results led to a LD of 3.550mg./kg. The slope of the regression line is S=l.09. The confidenceinterval is between 3386 and 3727 mg./ kg. for LD and near unity for theregression line. The LD of phenylbutazone was 1000 mg./kg.

Consequently, the new salt administered per os is not highly toxic;indeed, it is considerably less toxic than phenylbutazone.

The following table sums up this toxicological study.

LD in mg./kg. P.O.

(2) Investigation of antivisceralgic and analgesic properties For thisinvestigation, three tests were made on mice.

(a) Kosters acetic acid test.Injections of acetic acid cause painfulmanifestations in animals, such as twisting and stretching of the trunk.The reduction in the number of these reactions after administration ofthe product is in direct relationship to the antivisceralgic property ofthe product.

(b) Eddys hot-plate test.The pain reaction is produced by heatstimulation applied at the level of the plantar surface of the animals.The reaction time, which .increases after administration of the product,determines the analgesic power thereof.

(c) Heat stimulation test of tail (Amour and Smith).- A hot beam isconcentrated on the animals tail. The burning sensation appears after atime depending upon the analgesic value of the product.

The animals were given the three tests consecutively. The followingtables give the results obtained in relation to the results obtainedwith phenylbutazone, 1 hour and 5 hours after administration .of theproduct.

(a) Acetic acid test:

Percent inhibition of pain reactions Dose, mgJkg.

(per 0s) 1 h. after 5 h. after New Salt 500 70 75 Phenylbutazone 250 2354 (b) Hotplate test:

Percent analgesic Dose, mgjkg.

(per 0s) 1 h. after 5 h. after New salt 500 42 19 Phenylbutazone 250 100 (0) Test of Amour and Smith:

Percent analgesic Dose, mgJkg.

(per 0s) 1 h. after 5 h. after New salt 500 39 12 Phenylbutazoue 250 615 The analgesic activity of the new salt, bearing in mind itsphenylbutazone content, is considerably better than the analgesicactivity of phenylbutazone.

(3) Studies of antiphlogistic activity These experiments were performedon mice and rats distributed into uniform batches. To determineanti-inflammatory activity, regression of the oedema produced at thelevel of the plantar surface of the rear paws by an injection ofphlogogenic agent, kaolin or formaldehyde, was investigated.

(a) Kaolin test.Regression of the oedema is determined by the differencebetween the weights of the paws when they are dissected after sacrificeof the animals.

i heart by Langendorfs method and in a second phase on The resultsobtained with the new salt and with phenyl- (a) In the case of theisolated heart, injection of the butazone are given in the followingtables: new salt in progressive doses of from 50 to 500 cause no MICEdisturbance on coronary vasomotricity nor on the myo- Dose in mg /kgca'rdic fibre. Cardiac depression with a toxic dose 1 mg.)

' 5 is only momentary. Substance 250 375 500 750 (b) In the case of theanaesthetised dog, intraduodenal New Sm, percent 8 H 39 47 injection ofthe new salt at a rate of 6 tablets containing 0.20 g. of activesubstance caused no change in arterial pressure, respiration and renalvolume. The various reagents of the neurovegetative system (adrenalin,noradrenalin, acetylcholine) underwent no reduction of theirPhenylbutazone, percent New salt, perc eut RAT own tensional activity.

Regression It can therefore definitely be stated, so far as the new e, ty, o e salt 18 concerned, that: Code mgJkg. percent percent New Salt 5000 61 (1) its acute toxicity 1s less than for phenylbutazone;

""""""""""""" 750 o 99 (2) it has increased antivisceralgic andanalgesic activity;

E 0 93 (3) it has an improved anti-inflammatory activity, and 750 0 95Phenylbutazone 250 20 4 (4) unlike phenylbutazone, 1t has no harmfuleffect on 375 so 29 250 0 63 20 the gastric mucous membrane. 375 20 81The new salt can be used in human medicine as an anti-inflammatoryagent, to which end it can be presented in association with someconventional excipient or vehicle; more particularly, it can beassociated with an ex- (b) Formaldehyde oedema in mice:

Dose, Regression mg./kg. Mortality, ofoedema, ciplent for adminlstrationper os, for instance, for tab- Code Percent percent lets, or it can beoffered in gelule form. It can also be New salt: 100 0 7 offered insuppository .or pomade form for external use,

gag g The tablets can contain 200 mg. of the new salt and supggg g g?positories 400 mg. and the pomade can contain 5% by Phenylbutazone 50 0O 30 Welght of the lilew Salt 100 0 The following are typical examplesof pharmaceutical 328 8 44 compositions: 375 20 71 (1) Salt ofphenylbutazone of diethyl-amino ethyl- The anti-inflammatory activity ofthe new salt as comamide or p-chloro phenoxy acetic acid 0.40 pared withthe anti-inflammatory activity of phenyl- Witepsol excipient 2.30butazone is distinguished by a gr a er r g ssi n f For a uppositoryeighing 2 7O the kaolin oedema and by substantially equal activity onthe formaldehyde oedema. In the light of the relation- (2) iz Speclfiedabove ship between the toxicities of the two substances, the corn-Magnesium stearate 0.002 parison clearly favours the new salt. For agelatin-coated p111 contalmng 0.232

(4) Studies of activity on the gastric mucous membrane From 200 to 1000mg. per day has so far been found Daily intramuscular injections ofphenylbutazone for 6 a satisfactory posology. consecutive days at a rateof 150 mg./ kg. produced gastric We claim as our invention: ulcers infrom 20 to of the rats. Daily intramuscular 1. A pharmaceuticalcomposition comprising an efinjections of the new salt at a rate of 300mg./kg. in the fective amount of a compound of the formula & l n-H C O(H5Cz)zN-CHz-CHz-NHC OCH:OCl 1 t0 2 H20 same conditions do notaffect-the wall .of the stomach at together with a pharmaceuticallyacceptable diluent. all. 60 2. A pharmaceutical composition according toclaim (5) Investigation of cardiovasular activity 1 in a form selectedfrom the group consisting of tablets,

pills and suppositories.

3. A method of therapeutic treatment which comprises administering to apatient as an anti-inflammatory agent an effective amount of a compoundof the formula Investigation in a first phase on an isolated rabbits adog anaesthetised with chloralose gave the following results:

7 8 4. A method according to claim 3 wherein the said 2,541,651 2/1951Hoffer 260--311 compound is administered at a rate of 200 to 1000 mg. of2,562,830 7/ 1951 Stenzl.

the compound per day. 2,887,474 5/1959 Alter et a1 260-965 3,202,675 8/1965 Albertson 2603 10 References Cited P 5 ALBERT T. MEYERS, PrimaryExaminer 5 9,415 10 139 Hinsberg 260.411 3 FRIEDMAN, Assistant EXaminer1,068,083 7/ 1913 Scheitlin et a1 260--311 1,871,950 8/1932 Callsen260-311 2,345,385 3/1944 Dohrn et a1. 260-311 10 260-41013

